Vacuolar pathogens present interesting challenges to the host immune system. By residing in specialized organelles, they can evade canonical pathways used for innate immune detection and presentation of microbial antigens. To understand immunity to vacuolar pathogens that reside in unique vacuoles, we are using the respiratory pathogen Legionella pneumophila as a model organism to dissect early events that are important for immune detection. Legionella have an interesting intracellular lifestyle. They reside in a vacuole that initially avoids fusion with lysosomes, and then establish a vacuole derived from the host endoplasmic reticulum that supports bacterial replication. To further understand how mammalian hosts respond to vacuolar pathogens, we are using both Legionella mutants that have specific defects in host trafficking, and mutant mice that lack receptors that play a role in immunity to infection. The overall goal is to determine the function of pattern recognition receptors in the detection and clearance of Legionella pneumophila. Tlr signaling in response to Legionella will be investigated using in vivo and ex vivo assays. The role Nod protein family members play in Legionella detection will also be addressed. Emphasis will be placed on how Bircle-mediated responses restrict Legionella growth.